The overall objective of our application is to translate latest research findings about LRRK2, a key player in PD pathogenesis, into the drug discovery pipeline for novel PD therapeutics. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause thus far identified in both familial and sporadic PD. Since mutant LRRK2 proteins cause hyper-activation of LRRK2 in vitro and cytotoxicity in neurons, therapeutics targeting LRRK2 is likely to be highly effective for PD. We also reason that LRRK2 represents a rare opportunity for therapeutic development since it contains two druggable enzymatic modules (kinase domain and GTPase domain), potentially providing multiple sites for drug action. We propose to employ two complementary approaches to PD drug development targeting LRRK2. Specific Aim 1 is to use recombinant full-length LRRK2 for high throughput screening of existing drugs and additional chemical libraries for kinase inhibitors and for GTP binding blockers that will prevent LRRK2 activation through distinct mechanisms of action. Specific Aim 2 is to utilize a newly developed C. elegans model of PD for in vivo assays of LRRK2 inhibitors. Recent studies have demonstrated that C. elegans can serve as a powerful whole animal model for early-stage drug screening and validation. We have recently established transgenic C. elegans animals expressing mutant LRRK2 that manifest easily quantifiable phenotype of neurodegeneration and behavior impairment relevant to PD. This C. elegans model of LRRK2 linked PD will be used to validate and characterize the promising LRRK2 inhibitory compounds from the in vitro chemical screens. The resulting candidates of LRRK2 inhibitors may be further optimized for better efficacy and drug-like activities. A multi-disciplinary team consisting of two principal investigators and several collaborators with expertise in LRRK2 pathobiology, C. elegans biology, and drug discovery has been established. As a result, preliminary data have been generated to provide evidence that our proposed investigation is based on sound scientific principles. We believe that our proposed studies will likely facilitate the discovery of potential drug candidates targeting LRRK2, and upon further validation in mammalian models may lead to novel therapeutics for the treatment and prevention of PD. PUBLIC HEALTH RELEVANCE: Parkinson disease is a devastating and fatal brain disorder affecting many people in US. The current therapeutic options for PD are very limited and no cure exists for the disease. Because LRRK2 mutations are thus far the most frequent cause for both familial and sporadic PD, the LRRK2 based drugs will likely have a very broad impact in benefiting all PD patients. The significance of our proposed studies will be the possibility of discovering novel drug leads for the treatment and prevention of PD.